Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
Department of Psychology, University of Florida, Gainesville, Florida.
Int J Neuropsychopharmacol. 2018 Jul 1;21(7):677-686. doi: 10.1093/ijnp/pyy025.
Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement.
To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking.
We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin's ability to attenuate cued reinstatement.
While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking.
催产素可减少雄性和雌性大鼠可卡因觅药行为的线索复吸，但其潜在的神经生物学机制尚未被揭示。在这一任务上的大多数研究都集中在伏隔核核心中的催产素和多巴胺相互作用上。伏隔核核心是复发的关键神经基质，伏隔核核心中的催产素给药可减少对安非他命线索的复吸。此外，伏隔核核心从包括前额叶皮层在内的许多区域接受强烈的谷氨酸能神经支配。因此，我们假设催产素调节伏隔核核心中的突触前谷氨酸末梢，从而影响复吸。
为了开始评估这一假设，我们研究了伏隔核核心内催产素对该区域细胞外谷氨酸水平的影响。我们接下来确定直接将催产素注入伏隔核核心是否可以减弱可卡因觅药行为的线索复吸，其作用方式依赖于代谢型谷氨酸 2/3 受体。最后，我们测试了在特定部位给予催产素是否可以减少可卡因线索复吸。
我们发现，在反透析催产素后的几分钟内，伏隔核核心细胞外谷氨酸水平升高。在有可卡因自我给药史的雄性和雌性大鼠中，伏隔核核心和前额叶皮层中特定部位给予催产素会产生相反的效果，分别减少和增加线索复吸。mGlu2/3 拮抗剂 LY-341495 逆转了催产素减弱线索复吸的能力。
虽然催产素增加伏隔核核心谷氨酸的确切机制尚未确定，但目前的结果清楚地支持了催产素在伏隔核核心中调节谷氨酸能神经传递，从而影响可卡因线索觅药。
